(1) Field of the Invention
The present invention relates to the Cercopithecus aethiops (African green monkey) trace amine receptor 1, the nucleic acid encoding the receptor, and methods for identifying analytes that are agonists or antagonists of the receptor.
(2) Description of Related Art
Norepinephrine, dopamine, and serotonin are biogenic amine neurotransmitters that exert their effects through interactions with subfamilies of receptors that belong to the rhodopsin superfamily of G protein-coupled receptors (GPCRs). In addition to these biogenic amine neurotransmitters, there exists a class endogenous amines (“trace amines”) that are found in very low levels in the tissues of a wide variety of organisms, including humans. These trace amines, which include tyramine, β-phenylethylamine (β-PEA), tryptamine, and octopamine and which are chemically related to the biogenic amines, are produced both in the body and obtained from the diet from foods such as chocolate, aged cheese, beer, soy sauce, and wine.
Trace amines exert various pharmacological effects. For example, the role of trace amines as neurotransmitters in invertebrates has been well established and octopamine is thought to be the sympathetic nervous system counterpart to norepinephrine. While the role of trace amines as neurotransmitters in mammalian systems has not been thoroughly examined, trace amines have been found to affect the uptake or release of catcholamines, or 5-HT activity, at nerve endings. Because a number of drugs that stimulate trace amine receptors alter a person's perception of reality, trace amine receptors may have an important role in the brain's response or processing of sensory information. Thus, disruptions or alterations in the trace amine system may be involved in depression as well as other psychiatric and neurological disorders, including migraines and headaches (See Branchek and Blackburn, Curr. Opin. Pharmacol. 3: 90-97 (2003); Kim and Zastrow, Mol. Pharmacol. 60: 1165-1167 (2001)). For example, D'Andrea et al. (Neurol. 62: 1701-1705 (2004)) have found elevated levels of trace amines in the plasma of patients with cluster headaches and migraines. Their results suggest that receptors for trace amines may be involved in the etiology of migraines and headaches.
Mammalian trace amine receptors 1 have been cloned from the mouse (Borowsky et al., Proc. Natl. Acad. Sci. U.S.A. 98 (16), 8966-8971 (2001); GenBank NM—053205), rat (Bunzlow et al., Molec. Pharmacol. 60: 1181-1188 (2001); GenBank NM—134328), rhesus monkey (Miller and Madras, Neurosci Abstr. 10: 1 (2002); GenBank AY135366), and human (Bunzlow et al., ibid.; GenBank NM—138327). Trace amine receptors has been reviewed by Brancheck and Blackburn, Curr. Opin. Pharmacol. 3: 90-97(2003) and have been disclosed in WO 0172841, WO 0222801 and U.S. Pat. No. 6,783,973 to Bunzow and Grady, and WO 00734499 to Ogozalek et al.
The trace amine receptor 1 is a transmembrane protein comprising the classical GPCR structure: an extracellular or ligand binding domain, seven transmembrane domains, and a cytoplasmic domain which interacts with Gα of the set of heterotrimeric G proteins. In the inactive state, Gα is bound to GDP. When a trace amine binds to the ligand binding domain, a signal is transduced through the receptor which results in the GDP bound to Gα to be replaced by GTP and the Gα to dissociate from Gβ and Gγ (which remain as a GβGγ dimer). Gα and the GβGγ dimer activate effectors, which in turn, activate distinct intracellular pathways specific to the receptor and G protein. At present, more than five different Gα proteins subtypes are known; e.g., Gs, Gi/o, Gq, G12, and G13. Gs activates adenyl cyclase, Gi/o inhibits adenyl cyclase, and Gq activates phospholipase C beta (PLC) which cleaves phosphoinositol-4,5 bisphosphate (PIP2) in the cell membrane to release second messengers diacylglycerol (DAG) and inositol-(1,4,5)-triphosphate (IP3). G12 and G13 interact with Rho-specific guanine nucleotide exchange factors and regulate the actin cytoskeleton; however, G12 and G13 do not appear to have an important role in the function of GPCRs. Because stimulation of the human trace amine receptor 1 by various agonists produces an increase in cAMP accumulation, it is likely that the trace amine receptor 1 signals through a Gs-mediated signal transduction pathway (Borowsky et al., Proc. Natl. Acad. Sci. 98: 8966-8971 (2001)).
Because trace amines appear to be neurotransmitters with a role in various human psychiatric and neurological disorders, there is a need for methods for identifying agonists and antagonists of trace amine receptor 1 that can be used in therapies to treat the above disorders.